Many smokers use cigarettes as a means to combat stress. Removal of nicotine without addressing the underlying physiological changes associated with nicotine use results in an unbalanced system that compels a return to smoking to alleviate the withdrawal symptoms. Some of the behavioral and addictive properties of nicotine appear related to its activation of the hypothalamic-pituitary-adrenal (HPA) axis that is intimately involved in the stress response. Acute administration of nicotine has been shown to stimulate ACTH and corticosterone/cortisol secretion in both rodents and humans. The stimulation involves central mechanisms and corticotropin-releasing hormone (CRH) has been implicated as the mediator, but not shown to be required for the effect of nicotine. CRH and, to a lesser extent, arginine vasopressin (AVP) mediate the stress response. AVP also has a role in mediating the effects of nicotine on the HPA axis, as AVP-deficient rats have a severe blunting of ACTH to a nicotine-challenge. The stimulation of the HPA axis by nicotine may mediate some of the physiological and behavioral effects of nicotine. Additionally, a bi-directional interaction between nicotine and the HPA axis has been formulated based on the finding that corticosteroids attenuate some of the physiological and behavioral effects of nicotine. Thus, initial stimulation of the HPA axis may lead the smoker to increase his/her nicotine intake in order to maintain the stimulatory effects of nicotine on the stress response. The addicted smoker attempting to stop nicotine intake goes into a mild, yet unpleasant condition of glucocorticoid withdrawal, making smoking cessation less palatable. Thus, we propose that activation of the HPA axis is an integral part of the nicotine addiction process and understanding how nicotine interacts with the HPA axis will provide a basis for the rational development of novel treatments for nicotine addiction. Many questions about the link between nicotine and the HPA axis remain. Is CRH necessary to mediate the stimulation of ACTH release by acute nicotine? What is the role of AVP? How does chronic nicotine use stimulate the HPA axis? How important is the negative feedback on the axis by glucocorticoids? Most importantly, how does blockade of some of the arms of the HPA axis affect nicotine intake? The availability of new specific nicotine receptor antagonists, AVP-receptor antagonists and the non-peptide CRH-receptor antagonist, antalarmin, provide powerful tools to answering these questions experimentally. Adrenalectomy (with and without corticosterone replacement) allows us to study the role of glucocorticoids in nicotine-induced stimulation of ACTH and nicotine self-selection. These experiments should clarify the role of hypothalamic factors and glucocorticoids in the nicotine-induced stimulation of the HPA axis. The use of glucocorticoid synthesis inhibitors or antagonists, antalarmin, or other CRH and/or AVP antagonists, may be helpful in smoking cessation programs in humans.